Due to the high pharmacological, biological, biochemical, and diagnostic importance of nucleosides, facile methods for their modification is critical. SNAr displacement chemistry is a means of modifying nucleosides wherein a leaving group from the purine base is displaced by a suitable nucleophile.
Many compounds have resulted from SNAr displacement chemistry of nucleosides, ranging from adenosine receptor modifiers, anti-viral and anti-cancer agents, to carcinogen-nucleoside conjugates. These compounds have utilities ranging from potential pharmaceutical agents to probes of cellular response such as cancer causation. FIG. 1 shows some examples of modified nucleosides that have been synthesized using SNAr displacement chemistry.

Among the compounds in FIG. 1, compounds 1 and 2 were shown to be potent and selective adenosine A1 and A2B receptor agonists. Adenosine receptors are of high importance in cardiac, nervous system functions as well as immune systems. Compound 3 was shown to be active against the malarial parasite Plasmodium falciparum. Carbovir, compound 4, showed promising activity as an anti HIV drug and the carcinogen-nucleoside conjugate has been used to probe DNA damage structure in the search for the underlying cause of carcinogenesis.
SNAr displacement reactions on nucleosides are an important transformation for the synthesis of new nucleosides with a significant variety of applications. Convertible nucleosides that can be used for such chemistry include 6-halo nucleosides and in some cases arylsulfonyl derivatives of nucleosides.
Structures of typical convertible purine nucleosides are shown in FIG. 2. These compounds could be either in the ribo nucleoside or the deoxyribonucleoside series (leading to new ribo or deoxyribonucleosides). Alternatively, any other entity can be attached to the 9-position of a purine that contains a leaving group at position 6 (leading to substituted purine derivatives).

Among the halo nucleosides shown in FIG. 2, compounds 6 and 7 (R═H) are commercially available. Compound 7 is relatively expensive. Compounds 6 and 7 can be synthesized via known procedures, but the methodology involved is quite difficult. The bromo and iodo nucleosides, which are not commercially available, are easier to prepare than the chloro analogs, however, the syntheses are not simple.
The aryl sulfonate derivatives (compounds 12-15), which are not commercially available, also require relatively non-trivial syntheses. In particular, the aryl sulfonylation reactions of hypoxanthine nucleosides that lead to compounds 12 and 13 are quite complex. For example, in the absence of an amino group at the C-2 position, sulfonylation of the hypoxanthine core produces a significant amount of the N-1 sulfonyl derivative which results in a substantial loss of a costly precursor.
Some other nucleoside derivatives shown in FIG. 3 have been developed as convertible nucleosides. For examples of the syntheses, see Fathi et al., Tetrahedron Lett., 31, 319-322 (1990); Ferentz et al., Nucleosides & Nucleotides, 11, 1749-1763 (1992); Gao et al., J. Org. Chem., 57, 6954-6959 (1992); Zemlicka et al., Nucleosides & Nucleotides, 15, 619-629 (1996); Mechtild et al., J. Chem. Soc., Perkin Trans. 1: Org. Bio-Org. Chem., 1825-1828 (1997); Maruenda et al., J. Org. Chem., 63, 4385-4389 (1998). These compounds are either derived from the types of compounds shown in FIG. 2 or require independent syntheses, none of which are simple and/or readily scalable.

Recently it was shown that triphenylphosphine (PPh3) in combination with iodine (I2), N,N-diisopropylethyl amine (DIPEA) and either morpholine, piperidine or imidazole resulted in the conversion of hypoxanthine nucleosides to substituted adenine derivatives. See Lin et al., Org. Lett., 2, 3497-3499 (2000). Among these the imidazobil derivative 20 was found to be a useful convertible nucleoside. Subsequently, compound 21 was synthesized through a procedure similar to that leading to compound 20. The mechanism of this transformation is shown in Reaction Scheme 1. See Janeba et al., Nucleosides Nucleotides & Nucleic Acids, 7, 5877-5880 (2005).

Of key importance in Reaction Scheme 1 was the formation of the phosphonium salt which functioned as a convertible nucleoside, and which was formed in situ. Subsequently, the use of 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), a peptide coupling agent, was reported for the activation of hypoxanthine nucleosides (Reaction Scheme 2). See Wan et al., Org. Lett., 7, 5877-5880 (2005).

Convertible nucleosides are typically difficult to synthesize, and their prices are high as a result. Consequently, there is a need for convertible nucleosides that can be synthesized through the use of commercially available materials in an operationally simple and efficient protocol.